The use of cytotoxic agents is at the basis of the treatment of cancer and other pathological conditions. Ideally cytotoxic agents should accumulate at site of disease, sparing normal tissues. In reality this does not happen. Many anticancer drugs do not preferentially accumulate in solid tumors. Indeed, it has been demonstrated in tumor-bearing mice that only a minimal portion of the injected drug reaches the neoplastic mass in comparison to the amount of cytotoxic agent that reaches healthy organs.
The targeted delivery of highly potent cytotoxic agents into diseased tissues is therefore desirable for the treatment of cancer and other serious conditions. By attaching a therapeutic effector through a cleavable linker to a ligand specific to a marker of disease, the effector preferentially accumulates and acts at the intended site of action, thus increasing the effectively applied dose while reducing side effects. To date, monoclonal antibodies have been considered as the ligands of choice and, indeed, research in the field of antibody-drug conjugates (ADCs) has led to the recent approval of two ADCs for applications in oncology: brentuximab vedotin and trastuzumab emtansine.
However, antibodies are large macromolecules and thus often have difficulties penetrating deeply into solid tumors. In addition, they can be immunogenic and typically long circulation times can lead to premature drug release and undesired side effects. Moreover, the production of ADCs is expensive, reflecting the need for clinical-grade manufacturing of antibodies, drugs and the resulting conjugates.
The use of smaller ligands as delivery vehicles such as peptides or small drug-like molecules could potentially overcome some of the abovementioned problems. Their reduced size should aid tissue penetration, they should be non-immunogenic and amenable to classic organic synthesis thus reducing manufacturing costs. The favorable properties of drug conjugates using folic acid or ligands against prostate-specific membrane antigen (PSMA) as delivery vehicles have been demonstrated and a folate conjugate has recently entered Phase III clinical studies. However, only a few such conjugates have been successfully identified.
WO2006137092 describes the use of fluorophore-labeled Carbonic Anhydrase IX inhibitors for the treatment of cancers by inhibiting the activity of CAIX and thereby reversing acidification of the extracellular environment of the tumour. There is no suggestion to use the CAIX inhibitors for targeting cytotoxic agents. Further CAIX inhibitors for the treatment of cancer are described in WO2011098610 and WO2004048544.
The present inventors have found small molecule drug conjugates that target Carbonic Anhydrase IX (CAIX) expressing tumors.